Vasoactive intestinal peptide (VIP) is known to exist in the small intestine, reproductive system, and central nervous system. It has been isolated from the small intestine of the hog and from the intestine of other animals, including the chicken.
The amino acid sequence of VIP peptide derived from the intestine of the hog has been described as having the following amino acid sequence: ##STR1##
The conventional abbreviations for amino acids are the following:
______________________________________ Amino Acid Abbreviation ______________________________________ alanine Ala arginine Arg asparagine Asn aspartic acid Asp cysteine cys glutamic acid Glu glutamine Gln glycine Gly histidine His isoleucine Ile leucine Leu lysine Lys methionine Met norleucine Nle phenylalanine Phe proline Pro serine Ser threonine Thr tryptophan Trp tyrosine Tyr unknown or other amino acid Xaa valine Val ______________________________________
The amino acid units in VIP derived from animals are in the L-form.
VIP derived from other animals can differ somewhat in amino acid sequence. For example, VIP derived from the intestine of chicken varies from the above amino acid sequence of VIP derived from hog intestine as follows:
a serine residue in position 11, PA1 a phenylalanine residue in position 13, PA1 a valine residue in position 26 and PA1 a threonine residue in position 28.
It has been reported that VIP, e.g., VIP (hog) as described above, has systemic vasodilator activity. The effects of VIP and/or its analogs include systemic hypotension (European Patent Publication No. 0 241 926 A2) and increases cardiac output on intravenous infusion. VIP and/or its analogs have been reported to increase hepatic arterial blood flow and blood sugar levels, and to have the ability to bring about a bronchodilatory action (U.S. Pat. No. 4,734,400) and relaxation of gut smooth muscle, as well as stimulation of colonic motility, anti ulcer action, and the output of bicarbonate from intestinal secretion. VIP and/or its analogs also stimulate tear secretion (U.S. Pat. No. 4,745,100), hairgrowth (European Patent Publication No. 0 225 639 A2), vaginal lubrication (PCT/US87/03038) and increase in pulse rate and cutaneous flushing (PCT/US87/03038). It therefore appears to be useful in treatment of hypertension and peripheral vascular disease on parenteral administration, and as a bronchodilator on aerosol or parenteral administration (U.S. Pat. No. 4,737,487).
The following is a list of reported actions of VIP:
__________________________________________________________________________ ACTIONS OF VIP ACTION SITE OF ACTION SPECIES AUTHOR YEAR __________________________________________________________________________ cardiac output+ systemic dog Said, Mutt 75 respiratory stimulation systemic dog Said, Mutt 75 hyperglycemia systemic dog Said, Mutt 75 cyclic AMP+ pancreatic cells guinea pig Robberecht+ 76 blood pressure- systemic dog Said, Mutt+ 77 arterial blood flow+ systemic dog Said, Mutt+ 77 smooth muscle relaxation stomach rat Said, Mutt+ 77 smooth muscle relaxation trachea guinea pig said, mutt+ 77 smooth muscle motility+ colon rat Said, Mutt+ 77 water flow+ colon rat Waldman+ 77 cyclic AMP+ brain (amygdala) rat Quik+ 79 cyclic AMP+ mononuclear cells human Ottaway+ 83 ACTH, endorphin release pit. tumor cells mouse Westendorf+ 83 intraocular pressure- eye rabbit Mittag+ 87 adenylate cyclase+ arterial cells bovine Huang+ 84 glycogenolypis+ cortical slices mouse Magistretti+ 84 vasodilation 30 brain arteries human Suzuki+ 84 thyroid hormone secretion systemic mouse khren 85 bronchodilation bronchi human Palmer+ 86 neuronal hyperpolarization Schwann cell squid Evans+ amylase release+ colonic tumor rat Pandol+ 86 cyclic Amp+ gastric mucosa guinea pig Sutliff+ 86 pepsinogen secretion+ gastric mucosa guinea pig Sutliff+ 86 hair growth+ skin mouse Yanaihara+ 87 lubrication+ vagina human Fahrenkrug+ 88 chloride secretion+ colonic cells human McCabe+ 88 blood flow+ genital tract human Fahrenkrug+ 88 blood flow+ heart dog Smitherman+ 88 renin secretion rate+ kidney dog Porter+ 88 neuronal survival+ spinal cord cult. mouse fet. Brenneman 88 REM sleep+ brain (IV vent.) cat Drucker-Colin+ 88 somatostatin release+ dienceph. cells rat Reichlin 88 amylase release+ pancreatic acini guinea pig Musso+ 88 tear secretion+ eye rabbit Gilbard+ 88 progesterone secretion+ ovarian granulosa hen Johnson+ 88 androgen secretion+ ovarian granulosa hen Johnson 88 arterial relaxation uterus guinea pig Morris+ 89 __________________________________________________________________________ + = Stimulation - = Inhibition
Additionally, it has been reported that various VIP fragments, analogs and derivatives have various pharmacological activities.
It has also been reported that the intact VIP induced analgesia through the central nervous system when administered to rats directly into the periaqueductal gray matter (Sullivan, T. L. and A. Pert, [1981]. Soc. Neurosci. Abst. 7:504) or to the intrathecal space of the lumbo-sacral spinal cord (Komisaruk, B. R., C. Banas, S. B. Heller, B. Whipple, G. F. Barbato, and F. Jordan [1988] [Ed. S. I. Said and V. Mutt]. Ann. N.Y. Acad. Sci. 527:650-654). However, one study found that intrathecal injection of VIP reduced reaction time on a nociceptive test (Cridland, R. A. and J. L. Henry [1988]. Neuropeptides 11: 23-32).
It is desired that substantially smaller peptide segments of VIP analogs, derivatives or salts thereof be found which would induce analgesia through the central nervous system when administered to mammals. Such peptide segments would represent a substantial reduction in cost thereof and would provide other advantages, e.g., accessibility to the central nervous system, in view of the reduced length of the amino acid sequence of the peptide and molecular weight.